Cryptococcus neoformans infections are a leading mycological cause of morbidity and mortality among AIDS patients. Global estimates suggest that one million cases of cryptococcal meningitis occur each year resulting in over 620,000 deaths. Clinical and experimental evidence show that cell-mediated immunity (CMI) by CD4+ Th1-type cells constitutes the protective host defense response against C. neoformans infections. Consequently, it may seem counterintuitive to suggest that development of an effective anti-cryptococcal vaccine that 1) confers protection in the presence or absence of intact immunity and 2) induces protection that endures during the subsequent development of immune suppression is feasible. However, studies presented herein show that B cell deficient mice immunized with an IFN-?-producing C. neoformans strain, denoted H99?, and subsequently depleted of T cells were capable of mounting protective immune responses against an otherwise lethal pulmonary challenge with wild-type (WT) C. neoformans. These findings suggest that an innate population of immune cells can be induced to mount protective anti-cryptococcal immune responses in the absence of classical adaptive immunity. These results challenge our traditional model of adaptive and innate immunity in that innate cells are not considered to undergo rapid expansion to mediate enhanced effector cell function and protection in the absence of antigen-specific T and/or B cells. Identifying the innate cell population/s and mechanism by which protective anti-cryptococcal immune responses occurs in the absence of T and/or B CMI will mark a paradigm change from the classical dichotomy of adaptive versus innate immunity. We therefore hypothesize that innate immunity can be primed to provide protection against C. neoformans infection that endures during the absence of T and B cell-mediated adaptive immune responses. We plan to test our hypothesis by pursuing the following Specific Aims: (1) to identify the innate cell population(s) that confers protection against C. neoformans in the absence of classical adaptive immunity, and (2) to determine the mediators of anti-cryptococcal activity of innate cells isolated from immunized, T and B cell deficient mice.